Certain behavioral disorders are largely treated with psychological counseling or behavioral therapies, such as certain addictions, obsessive-compulsive disorder, Tourette's syndrome, autism spectrum disorder, schizophrenia, post-traumatic stress disorder (PTSD), anxiety disorders, and other disorders involving troubling memories. Even in disorders for which pharmaceutical treatment is available, such as bipolar disorder, depression, and schizophrenia, counseling is used as an adjunct.
Behavioral disorders are difficult to treat and often result in relapse. A number of behavioral disorders have been treated with varying degrees of success by repeatedly exposing patients to situations that elicit symptoms of these disorders. Drug and alcohol addiction have been treated with limited success using a “cue elicited craving paradigm” which involves presenting addicts with drug-related cues (e.g., videotapes, audiotapes, actors performing simulated drug administration rituals, pictures or slides of white powder, crack pipes, bar scenes, etc.) designed to elicit craving. This exposure treatment aims to reduce the tendency for patients to respond to these situations.
Animal models of anxiety disorders have been used to screen for drugs that promote the reduction of conditioned fear. For example, D-cycloserine, a drug that promotes NMDA receptor activity, was found to facilitate the reduction of conditioned fear (Davis et al., Biol. Psychiatry 51:1S, 2002; Walker et al., J. Neurosci. 22:2343-2351, 2002). However, an obstacle for this treatment approach is that symptoms of anxiety disorders can show resistance to extinction (Poulton R, et al. Behav. Res. Ther. 39:29-43, 2001; Poulton R and Menzies R G. Res. Ther. 40:197-208, 2002). Repetitive transcranial magnetic stimulation (rTMS) was also developed as a noninvasive method of altering the excitability of neuronal circuitry in the brain. Preliminary studies of patients with focal dystonia, epilepsy, PTSD, depression, or schizophrenia have revealed modest symptom reductions after rTMS treatment.
Oxytocin (OT) has also been implicated as a potential factor in certain psychiatric disorders. For example, based on a review of evidence from animal studies demonstrating that altered OT and vasopressin have unique effects on the normal expression of species-typical social behavior, communication, and rituals, Insel and colleagues have proposed that altered OT or vasopressin neurotransmission may account for several features associated with autism. See Insel et al., Biol. Psychiatry 45:145-157, 1999. A study on autistic children reported that such children had significantly lower levels of plasma OT than normal children. Elevated OT levels were associated with higher scores on social and developmental tests in non-autistic children, but associated with lower scores in autistic children, suggesting that altered OT levels may be associated with autism in children (Modahl et al., Biol. Psychiatric 43:270-277, 1998). A role for OT in obsessive compulsive disorders has also been proposed (Leckman et al., Psychoneuroendocrinology 19:723-749, 1994; but see Altemus et al., Biol. Psychiatry 45:931-33, 1999, see also U.S. Patent Publication 2006/0105939).
In particular, elevated levels of OT have been proposed to affect certain obsessive-compulsive behaviors, such as excessive worrying, sexual compulsions and/or compulsive washing and cleaning. (Leckman et al., Psychoneuroendocrinology 19:723-749, 1994; Leckman et al., Arch Gen Psychiatry 51:782-92, 1994). Elevated levels of OT have also been implicated in Prader-Willi syndrome, a genetic disorder associated with mental retardation, appetite dysregulation, and a risk of developing obsessive compulsive disorder (Martin et al., Biol. Psychiatric 44:1349-1352, 1998).
Elevated levels of the peptide OT have been associated with the onset of pro-social behaviors. Exogenously administered OT enhances prosocial behavior and social information processing in animal models, and intranasal OT enhances some aspects of social cognition in humans suggesting that the OT system may be a viable target for pharmacological therapies for disorders characterized by social deficits, like autism spectrum disorders and schizophrenia. In non-clinical populations, intranasal OT has been shown to increase trust, generosity, empathy, socially reinforced learning, (Hurlemann et al, 2010 J. Neurosci., 30:4999) and attention to and comprehension of emotional expression. Administration of intranasal OT to individuals with autism spectrum disorder, has recently been found to increase social interactions and feelings of trust toward cooperative individuals and time spent gazing at the eye region of a social partner in a social cooperative game (Andari et al., Proc Natl Acad Sci USA, 2010, 107:4389-4394) and to increase the ability to interpret emotional expression (Guastella et al., Biol Psychiatry, 2008, 63:3-5). References cited herein are not an admission of prior art.
Social bonding in voles is a useful behavioral paradigm to assess the social cognitive enhancement properties of drugs. OT appears to increase the saliency of social stimuli and to enhance social information processing, and may also tag social stimuli with a reinforcing state. OT also has a role in decreasing anxiety-like and anxiety behaviors. In humans, nasal OT administration has been shown to decrease the level of the stress hormone cortisol and enhance positive behavioral aspects. OT dysfunction has been implicated in schizophrenia. Patients with schizophrenia have been shown to have a decreased level of OT in their blood.
Intravenous OT administration has resulted in modest behavioral effects in individuals with autism spectrum disorder (ASD) as only a small fraction of the peptide is able to cross the blood-brain-barrier due to the poor permeability of the peptide. Neuropharmacological studies have recently suggested that OT gains better access to the brain through intranasal administration. Though, while many behavioral studies have been conducted using this technique, no study to date has shown an increase in central OT levels following intranasal dosing.
Although administration of OT has been attributed positive mood in humans, OT is a large peptide that does not effectively cross the blood brain barrier. Because OT does not cross be blood brain barrier effectively, there is a need to develop a more efficient means of increasing the levels and effectiveness of OT in the brain.
A number of OT analogs have been evaluated, largely as possible substitute agents for inducing uterine contraction and milk let-down, rather than to enhance brain penetration and activity (Atke et al., Acta Endocrinol. 115:155-160, 1987; Norstrom et al., Acta Endocrinol. 122:566-568, 1990; Hunter et al., Clin. Pharmacol. Ther. 52:60-67, 1992; Silcox et al., Obstet Gynecol. 82:456-459, 1993; Vilhardt et al., Pharmacol. Toxicol. 81:147-150, 1997; Boucher et al., J. Perinatology 18:202-207, 1998).
Melanocortin receptors are localized on OT neurons, and stimulation of these receptors has been shown to stimulate the release of oxytocin within the brain (Sabatier et al., J Neuroscience, 2003, 23(32):10351-10358). Melanocortin receptor-specific compounds have been explored for use of treatment of sexual dysfunction. A cyclic melanocyte-stimulating hormone (“alpha-MSH”) analog, called Melanotan-II, was evaluated for erectogenic properties for the treatment of men with psychogenic erectile dysfunction. OT also has erectogenic properties, and the release of OT may be one mechanism underlying this effect of MTII. Wessells et al., J Urology 160:389-393 (1998); see also U.S. Pat. Nos. 5,576,290 and 6,051,555. The peptides used in U.S. Pat. Nos. 5,576,290 and 6,051,555 are also described in U.S. Pat. No. 5,674,839, issued Oct. 7, 1997, to V. J. Hruby, M. E. Hadley and F. Al-Obeidi, entitled Cyclic Analogs of Alpha-MSH Fragments, and in U.S. Pat. No. 5,714,576, issued Feb. 3, 1998, to V. J. Hruby, M. E. Hadley and F. Al-Obeidi, entitled Linear Analogs of Alpha-MSH Fragments. Additional related peptides are disclosed in U.S. Pat. Nos. 5,576,290, 5,674,839, 5,714,576 and 6,051,555. These peptides are described as being useful for both the diagnosis and treatment of psychogenic sexual dysfunction in males and females. These peptides are related to the structure of melanocortins. Other peptides are disclosed in U.S. Pat. Nos. 6,284,735 and 4,649,191, and U.S. Published Patent Applications Nos. 2001/0056179 and 2002/0004512.
There remains a need for improved therapeutic modalities for treatment of behavioral disorders. It is an object of this disclosure to provide treatment methods for improving the outcome of therapeutic treatments of a behavioral disorder. It is a further object of the disclosure to provide a method of mood elevation and enhancement of social cognition in a subject in need thereof.